The early retinal progenitor-expressed gene Sox11 regulates the timing of the differentiation of retinal cells

Abstract

SUMMARYSry-related HMG box (Sox) proteins, Sox11 and Sox4 are members of the SoxC subtype. We found that Sox11 was strongly expressed in early retinal progenitor cells and that Sox4 expression began around birth, when expression of Sox11 subsided. To analyze the roles of Sox11 and Sox4 in retinal development, we perturbed their expression patterns in retinal explant cultures. Overexpression of Sox11 and Sox4 in retinal progenitors resulted in similar phenotypes: an increased number of cone cells and dramatically decreased numbers of rod cells and Müller glia. Birth-date analysis showed that cone cells were produced at a later developmental stage than that in which cone genesis normally occurs. Sox11-knockout retinas showed delayed onset and progress of differentiation of subsets of retinal cells during the embryonic period. After birth, retinal differentiation took place relatively normally, probably because of the redundant activity of Sox4, which starts to be expressed around birth. Overexpression and loss-of-function analysis failed to provide any evidence that Sox11 and Sox4 directly regulate the transcription of genes crucial to the differentiation of subsets of retinal cells. However, histone H3 acetylation of some early proneural genes was reduced in knockout retina. Thus, Sox11 may create an epigenetic state that helps to establish the competency to differentiate. Taking our findings together, we propose that the sequential expression of Sox11 and Sox4 during retinogenesis leads to the fine adjustment of retinal differentiation by helping to establish the competency of retinal progenitors.

Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis

“…However, the perinatal lethality of Sox11 null mice has precluded a thorough in vivo assessment of rod photoreceptor differentiation, which mostly occurs postnatally. Expression of the rod photoreceptor genes Nrl , Nr2e3 , and Sag (Rod arrestin) is significantly reduced in E16 retinas from Sox11 −/− mice [51], suggesting that Sox11 does regulate aspects of rod photoreceptor differentiation in mammals. However, in retinal explants derived from Sox11 null mice and cultured for several days, reduced rod photoreceptor number was not observed [51].…”

Transcription Factors SOX4 and SOX11 Function Redundantly to Regulate the Development of Mouse Retinal Ganglion Cells

“…Previous studies on their potential functions in development have been mainly focused on their roles in maintaining the differentiation ability of progenitor cells and promoting cell proliferation. Overexpression of Sox4 or Sox11 in cultured retinal explants at E17 stimulates the differentiation of progenitor cells into cone cells at the cost of losing rod cells (23). Abrogation of Sox4/11 in vivo suppresses the differentiation of adult neuron stem cells and does not affect the apoptosis (20).…”

“…The broad expression of SoxC genes has been reported in neural progenitor cells and mesenchymal cells in variant tissues during development (13,14), and they have been found to regulate cell differentiation, proliferation and survival in multiple organ lineages (16 -22). Recent studies on Sox4 and Sox11 imply their roles in retinal cell differentiation (23). However, the regulation of RGC development by the two genes has not been determined.…”

Can the ‘neuron theory’ be complemented by a universal mechanism for generic neuronal differentiation

“…Sox4 becomes detectable at E11.5 and both are modestly expressed in the neuroblast layer as compared to high levels in the ganglion cell layer. Retrovirus-mediated Sox11 overexpression in retinal explant cultures appears to induce increased generation of RXRγ-positive cone cells that do not, however, pass through final maturation as shown by the lack of M-opsin and cone arrestin 4 (Usui et al 2013). The generation of rhodopsin-positive rod cells is suppressed.…”

“…Sox11 transcripts are already widely expressed in mouse optic cup and retina at E10.5 (Jiang et al 2013). At E11, some Sox11-expressing cells exhibit ß-III tubulin signals (Usui et al 2013). Sox4 becomes detectable at E11.5 and both are modestly expressed in the neuroblast layer as compared to high levels in the ganglion cell layer.…”